Daily use of marijuana use is increasingly common in persons living with HIV (PLWH). In Florida, which continues to have one of the highest rates of HIV incidence and prevalence in the US, voters are expected to pass an amendment to legalize medical marijuana for use by PLWH in late 2016. While there is some evidence that marijuana can improve HIV-related symptoms, there is almost no existing evidence regarding the long- term health effects of marijuana in PLWH. Marijuana, which contains a number of different cannabinoid products, could affect HIV health outcomes via both behavioral mechanisms (e.g. medication adherence, motivation) and biological mechanisms (e.g. anti-inflammatory, viral suppression). The overarching goals of this study are to obtain evidence regarding the influence of marijuana on major health outcomes and behavior in PLWH in order to help guide clinical recommendations and identify risk factors for consequences. We are especially interested in the relationship of marijuana to novel aspects of cognitive function (e.g. motivation, intention, planning) and to systemic inflammation. To accomplish these research goals, we propose a new, longitudinal cohort of 480 PLWH (160 regular marijuana users, 160 occasional marijuana users, and 160 non- users). We will obtain detailed marijuana assessments, including cannabis biomarkers, together with repeated measures of cognition, systemic inflammation, and HIV care engagement and health outcomes. Our Specific Aims are: 1) To prospectively determine the association of daily and occasional marijuana use with HIV care engagement, viral suppression, and HIV disease progression; 2) to prospectively determine the association of past and current marijuana use with cognitive function, motivation, and planning; and 3) to prospectively determine the association of chronic marijuana use with cytokine markers of chronic inflammation. For each of these aims, we will conduct subgroup analyses to explore whether these relationships vary by individual characteristics such as gender and age (>50 vs. <50), and by characteristics of past and current marijuana use, including cannabis use disorder. This will be the largest prospective cohort study focused on the health effects of marijuana in PLWH. The findings will inform HIV treatment providers and patients who are considering marijuana to manage HIV-related symptoms or HIV disease itself, and will identify patterns of marijuana use that are most strongly associated with the incidence of substance use disorders. Our research team is multidisciplinary, our infrastructure is in place, and our preliminary data support the need for this project. The research is consistent with current NIH HIV research priorities to reduce HIV transmission (by successful treatment and viral suppression) and to reduce the onset of HIV-related comorbidities, including cognitive dysfunction.